Biodegradable branched polylactide derivatives capable of forming polymeric micelles, and their preparation method and use

Abstract

The present invention relates to a biodegradable branched polylactic acid derivative of formula 1, and preparation method and use thereof: <formula 1> 1-(R—X) n wherein each of X, R, I and n is defined as in the detailed description.

1. A micellar composition comprising a branched polylactic acid derivative of formula (I) for forming micelles in an aqueous solution with a pH of 4 or more:
   I—(R—X) n   (1)
 
 Wherein, 
 R is —[R 1 ] k —[R 2 ] m —, 
 wherein R 1  is —C(═O)—CHZ—O—,
 R 2  is selected from the group consisting of —C(═O)—CHY—O—, —C(═O)—CH 2 CH 2 CH 2 CH 2 CH 2 —O— and —C(═O)—CH 2 —O—CH 2 CH 2 —O—, wherein each of Z and Y is selected from the group consisting of hydrogen, methyl, and phenyl, 
 
 k is an integer of 1-30, 
 m is an integer of 0-30;
 X is —C(═O)—(CH 2 ) a —C(═O)—O-M, wherein a is an integer of 0-10, M is selected from the group consisting of hydrogen, sodium, potassium, and lithium; 
 I is a diol or a polyol having 3-12 hydroxy groups; 
 
 n is the same as the number of hydroxy groups that I has, and wherein I is selected from the group consisting of ethylene glycol, propanediol, butanediol, pentanediol, hexanediol, glycerol, erythritol, threitol, pentaerythritol, xylitol, adonitol, sorbitol, mannitol, disaccharide and trisaccharide, and wherein the branched polylactic acid derivative has a number average molecular weight of 1,000-18,000 Dalton. 
 
     
     
       2. The micellar composition according to  claim 1 , wherein R is mono polymer or copolymer which is one or more selected from the group consisting of lactide, glycolide, caprolactone, 1,4-dioxane-2-one, and mandelic acid. 
     
     
       3. The micellar composition according to  claim 1 , wherein M is sodium, potassium or lithium. 
     
     
       4. The micellar composition according to  claim 1 , wherein the disaccharide is selected from the group consisting of palatinose, maltose monohydrate and maltitol, and the trisaccharide is D-raffinose pentahydrate. 
     
     
       5. A method of preparing the polylactic acid derivative described in any one of  claims 1  and  2  to  4 , comprising the steps of
 1) polymerizing a monomer of lactides in the presence of an initiator and a catalyst to obtain a branched polylactic acid; 
 2) dissolving the branched polylactic acid obtained in step 1) in a water-miscibile organic solvent, purifying the branched polylactic acid by adding an aqueous solution with a pH of 7 or more, and drying in vacuum, to obtain a powder form of the branched polylactic acid; and 
 3) reacting the branched polylactic acid derivative obtained in step 2) with succinic anhydride or a dichloride compound to obtain the branched polylactic acid derivative containing terminal carboxy group, wherein the initiator of step 1) is selected from the group consisting of ethylene glycol, propanediol, butanediol, pentanediol, hexandiol, glycerol, erythritol, threitol, pentaerythritol, xylitol, adonitol, sorbitol, mannitol, disaccharide and trisaccharide, and wherein the branched polylactic acid derivative has a number average molecular weight of 1,000-18,000 Dalton. 
 
     
     
       6. The method according to  claim 5 , further comprising the step of adding an alkali metal salt to the branched polylactic acid derivative obtained in step 3) to obtain the branched polylactic acid derivative containing carboxy alkali metal salt terminal group. 
     
     
       7. The method according to  claim 5 , wherein the disaccharide is selected from the group consisting of palatinose, maltose monohydrate and maltitol, and the trisaccharide is D-raffinose pentahydrate. 
     
     
       8. The method according to  claim 5 , wherein in step 3, the branched polylactic acid derivative is reacted with a compound which is selected from the group consisting of succinic anhydride, oxalyl chloride, malonyl chloride, succinyl chloride, glutaryl chloride, adipoyl chloride, sebacoyl chloride, and dochecadioyl dichloride. 
     
     
       9. The method according to  claim 6 , wherein the alkali metal salt is selected from the group consisting of sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate, and lithium carbonate. 
     
     
       10. The micellar composition according to any one of  claims 1  and  2 - 4 , wherein said composition is for a poorly, water-soluble drug delivery agent. 
     
     
       11. A pharmaceutical composition containing the polylactic acid derivative described in any one of  claims 1  and  2  to  4  and a poorly, water-soluble drug. 
     
     
       12. The micellar composition according to  claim 1 , wherein said branched polylactic acid derivative entrap drugs in the micelles by forming stable micelles in aqueous solution and solubilizing poorly water-soluble drugs within the micelles.